Certain derivatives of 5,6-diphenyl pyrazinylmalonates and pyrazineacetic acids

ABSTRACT

The compounds are of the class of pyrazine, arylpyrazine, diphenylpyrazine, and cycloalkylpyrazine malonates, acetates, acetamides, and acetic acids, useful for their ultraviolet light absorption properties.

United States Patent [191 Schwartz et a].

451 Aug. 26, 1975 CERTAIN DERIVATIVES OF 5,6-DIPHENYL PYRAZINYLMALONATES AND PYRAZINEACETIC ACIDS [75] Inventors: Norman Schwartz, Philadelphia;

Richard J. Mohrbacher, Fort Washington, both of Pa.

[73] Assignee: McNeil Laboratories, Incorporated,

Fort Washington, Pa.

22 Filed: Nov. 17,1972

21 Appl. No.: 307,681

Related U.S. Application Data [62] Division of Ser. No. 774,486, Nov. 8, 1968, Pat. No.

[52] U.S. Cl 260/250 B; 424/250; 260/458 N [5|] Int. Cl. C07D 241/02 [58] Field of Search 260/250 B, 250 R [56] References Cited UNITED STATES PATENTS 3,006,918 lO/l96l deJongh et al 260/250 Primary EraminerNicholas S. Rizzo Attorney, Agent, or FirmSalvatore R. Conte 5 Claims, No Drawings CERTAIN DERIVATIVES OF 5.6-DIPHENYI. PYRAZINYLMALONATES AND PYRAZINEACETIC ACIDS This is a divisional application of my co-pending application Ser. No. 774,486, filed Nov. 8. 1968, now issued as U.S. Pat. No. 3,761,477.

' This invention relates to certain novel pyrazineacetic acids, acetates, and acetamides. More particularly. this invention is concerned with arylpyrazine and cycloalkylpyrazine malonates. acetates. acetamides. and acetic acids having the formulae H N f X R R2 wherein R is a member selected from the group consisting of phenyl. chlorophenyl. dichlorophenyl, fluorophenyl. trifluoromethylphenyl. loweralkoxyphenyl. diloweralkoxyphenyl. loweralkylphenyl. diloweralkylphenyl. cyclohexyl and cyclopentyl; R, is a member selected from the group consisting of hydrogen and loweralkyl; R is a member of the group consisting of hydrogen. loweralkyl, loweralkyl carboxylate ester. and sodium. calcium. and ammonium carboxylate salts; and X is a member selected from the group consisting of loweralkyl carboxylate ester. carboxylic acid. carboxamide. a member selected from the group consisting of N-loweralkyl-. N.N-diloweralkyl. N-aryl-. N-aralkyl-. and N-heterocyclic-substituted carboxamides. and sodium. calcium and ammonium carboxylate salts; wherein when R is respectively loweralkyl carboxylate ester or carboxylate salt. X is also respectively loweralkyl carboxylate ester or carboxylate salt.

This invention is also concerned with pyrazine malonates. acetates. and acetic acids having the formula:

wherein R, is a member selected from the group consisting of hydrogen and loweralkyl; R is a member selected from the group consisting of hydrogen. loweralkyl. loweralkyl carboxylate ester. and sodium. calcium, and ammonium carboxylate salts; and Z is a member selected from the group consisting of loweralkyl carboxylate ester. carboxylic acid. and sodium. calcium. and ammonium carboxylate salts; wherein when R is respectively loweralkyl carboxylate ester or carboxylate salt. Z is also respectively loweralkyl carboxylate ester or carboxylate salt.

This invention is further concerned with diphenylpyrazine malonates. acetates. acetamides and acetic acids having the formula:

,1 C-)( G S l i 2 (III) C H5 N wherein R, is a member selected from the group consisting of hydrogen and loweralkyl; R is a member selected from the group consisting of hydrogen. loweralkyl. loweralkyl carboxylate ester. and sodium. calcium. and ammonium carboxylate salts; X is a member selected from the group consisting of loweralkyl carbox ylate ester, carboxylic acid. carboxamide. a member selected from the group consisting of N-loweralkyl-. N.N-diloweralkyl, N-aryl-. N-aralkyl-. and N-heterocy clic-substituted carboxamides, and sodium. calcium. and ammonium carboxylate salts; and wherein when R is respectively loweralkyl carboxylate ester or carboxylate salt. X is also respectively loweralkyl carboxylate ester or carboxylate salt.

The term loweralkyl' includes alkyl groups containing 1 to 7 carbon atoms. and preferably 1 to 4 carbon atoms. including saturated aliphatic chains. straight or branched. such as methyl. ethyl. propyl. isopropyl. nbutyl. and isobutyl.

The compounds of this invention absorb ultraviolet light and are useful as sun-screening materials in salves and ointments. In addition. because of their solubility in organic materials generally. they may be used as'ul' traviolet absorbers in plastics and resins. such as polystyrene. polyethylene. polypropylene. polyacrylics (methacrylate resins. polyacylamides. polyacrylonitrile fibers]. polyamide fibers (nylon e.g.). and polyester fibers. In the latter use. the inclusion of 0.01 to 5 percent of the absorber. based on the polymer weight. is sufficient to render protection against ultraviolet light. such as in plastic film or light filters. The absorber may be incorporated in the mixtures of monomers before polymerization to form the polymer or it may be incorporated in the polymer at any stage during its handling. as by milling into the polymer together with other compounding ingredients or during the spinning of polymers into fibers. etc.

Due to the asymmetric center present in the subject compounds wherein R, and R are different. except where R is identical with X or Z. it is evident that the existence of such compounds in the form of resolved enantiomorphs is possible. It is naturally intended that such enantiomorphs are included within the scope of this invention.

Compounds of Formula I and Formula ll. wherein R, is hydrogen or loweralkyl. R is loweralkyl carboxylate. and X and Z is loweralkyl carboxylate are prepared by reacting the appropriate 2-chloropyrazine derivative with diloweralkyl malonate or diloweralkyl loweralkylmalonate in the presence of sodium hydride in a suitable solvent such as dimethylformamide. As an alternative process. sodamide and liquid ammonia may be em ployed in place of sodium hydride and dimethylformamide.

Compounds of Formula I and Formula II wherein R, and R are both hydrogen or R, is hydrogen and R is loweralkyl and X or Z is loweralkyl carboxylate are prepared by heating the foregoing diloweralkyl pyrazinylmalonate and diloweralkyl a-loweralkylpyrazinylmalonate derivatives in a suitable solvent such as dimethyl sulfoxide in the presence of sodium cyanide.

Compounds of Formula I and Formula II wherein R ylate art re-pared by reacting a loweralkyl halide. such as methyl. ethyl. isopropyl or n-butyl iodide. with the aforementioned loweralkyl a-loweralkylpyrazineacerates in the presence of sod-amide in liquid ammonia.

and R are both hydrogen or R is hydrogen and R is 5 As an alternative, the lower-alkyl a-loweralkylpyrazinloweralkyl and X or Z is carboxylic acid are prepared cacetates may be reacted with sodium hydride in di by refluxing the foregoing loweralkyl pyrazineacetate methylsulfoxide followed by reaction of the anion thus and loweralkyl a-loweralkylpyrazineacetate derivatives produced with a loweralkyl halide, preferably the ioin aqueous sodium hydroxide and acidifying the resultdide.

ing hydrolyzate. In an alternative procedure the m The compounds of Formula I and II wherein R and pyrazineacetic acid derivatives may be prepared by R are each loweralkyl and X or Z are loweralkyl cartreating the diloweralkyl pyrazinylmalonates and the boxylate may be converted to the corresponding acetdiloweralkyl a-loweralkylpyrazinylmalonates of Foramides and acetic acids by the procedures described u fl l nd F rmula U t a as u h aqueous hereinbefore for the compounds wherein R is loweraldium hydroxide, and thereafter acidifying the solution. kyl and R is hydrogen.

Compounds of Formula I wherein X is carboxamide The N-substituted acetamides of this invention may are prepared by reacting the aforesaid pyrazineacetate be prepared by reacting the corresponding acetic acid and a-loweralkylpyrazineacetate derivatives with amderivatives of this invention with thionyl chloride and monium hydroxide. then with the desired amine.

In an alternative procedure, loweralkyl esters of the The salts of the acetic acid derivatives of this invenacetic acids of Formula I and Formula Il may be pretion may be prepared by reacting the corresponding pared from the corresponding acids by conventional acid in water with sodium. calcium, or ammonium hyesterification procedures. In another alternative procedroxide. dure, the acetamides of Formula I may be reacted with Compounds of the Formula II] are prepared in the aqueous hydrochloric acid. avoiding excess temperasame manner as in the case of compounds of Formula tures, or with sodium or ammonium hydroxide and l and Formula II, using 5-chloro-2.3-diphenylpyrazine thereafter. acidifying to form the corresponding as the starting material. pyrazineacetic acid derivatives. The following schematic diagram, exemplifying the Compounds of Formula I and I] wherein R and R preparation of Formula I type compounds. illustrates are each loweralkyl and X or Z are loweralkyl carboxthe foregoing syntheses:

I N l CHCO E! N 2 ci a I R l N 2 dicthyl loweralkyl OM50 l'l clona'c Nal'l a N 1 +Nu and our CHCO 2 it or R I iodqmid. and liquid ammonia R N NuCN DMSO I l l on: 1 NcOH N (2mm NcOH;

than ccidil l l R 1 CHCONH 2 E1 HCOOH NcOH and acidiy thion l chlarido;

cr arclkyl amines (mono--or di--substitution) The following schematic diagram illustrating the sis of the novel compounds of this invention: preparation of the suirting materials used in the synthe- 20 H O l 2 HC n \0 H N N OH c1 NuOH PO0 methanol, I prossur. Othunol, or and hour water a N R N H H N CONH 2 2 2 a o 2 \o I! H N N CNH2 R N OH I docurboxyluto A aox H 50 R N on 180%. i N

R N c POCI prossuru and heat and heat *ixcopt when R is cyclohoxyl.

| CH COOH CHCOBr r2 Para 0 Nl-l Nll NuOH N K c1 POCl a pressure and heal The following examples are intended to illustrate, but while the temperature is maintained at -3() C. The not to limit. the scope of the present invention. temperature is raised to between 2() and -l() for V2 EXAMPLE l 60 hour, to 0 for 2 hours. and finally to room temperature for 2 hours. lhe reaction mixture is then cooled in an To a mixture of phenylglyoxal hydrate (4L5 g., 0.27 ice-bath and treated dropwise with 45 ml. of concenmole) in 250 ml. of methanol at 4() (dry ice-carbon tratcd hydrochloric acidv The pH of the mixture is adtetrachloride-acetone) is added, with stirring. glycinajusted to 5 by the portionwisc addition of 27 g. of somide hydrochloride (30.0 g. (L27 mole) in 250 ml. of 6S dium bicarbonate. The mixture is filtered. The solid methanol, precooled to 4()C. To this stirred mixture material is recrystallized from n-hutanol. The product 50 ml. of V2.5 N sodium hydroxide is added dropwise is fi-phenylpyrazinol; m.p. 2()82l() C.

EXAMPLE n p-Chlorophenylglyoxal hydrate is prepared in two steps of oz-bromo-p-chloroacetophenone as described by Kornblum and Frazier [1. Am. Chem. Soc.. 88. 865 (1966)]. To the pchlorophenylglyoxal hydrate (26.5 g.. 0.14 mole) in 130 ml. of methanol cooled to -30 is added. with stirring, glycinamide hydrochloride 15.7 g.. 0.14 mole) in 130 ml. of methanol precooled to 30 C. To the stirring mixture is added dropwise 26 ml. of 12.5 N sodium hydroxide while the temperature is raised and is maintained at to 0 C. for 2 hours. The mixture is then stirred at ambient temperature for 2 /2 hours. Concentrated hydrochloric acid (24 ml.) is added dropwise to the mixture with ice-bath cooling. This is followed by the portionwise addition of sodium bicarbonate g.). The reaction mixture is refrigerated overnight. filtered and the solid is washed with water and recrystallized from 95 percent ethanol. The product is 5-( p-chlorophenyl )pyrazinol; m.p. 21 822 l C.

EXAMPLE 111 concentrated ammonium hydroxide, followed by the addition of 50 percent sodium hydroxide to make the mixture basic. The mixture is filtered through celite, the layers are separated. and the aqueous layer is extracted twice more with chloroform. The combined chloroform extracts are dried (Na SO and evaporated. The solid material is recrystallized from methanol. The product obtained is 2-chloro-5- phenylpyrazine; m.p. 96-98 C.

EXAMPLE IV A sodium hydride-mineral oil suspension (547r, 28 g.. 0.62 mole) is stirred with three 150 ml. portions of dry hexane (Na SO each portion being pipetted out to remove the mineral oil. Dimethylformamide (previously distilled and dried over a molecular sieve; 180 ml.) is added through a pressure equalized addition funnel while a slow stream of nitrogen is passed through the mixture. The reaction vessel is cooled in an ice-bath and diethyl methylmalonate (99.5 g.. 0.57

mole) is added dropwise to the stirred mixture. After addition is complete. the ice-bath is replaced by an oil bath and the temperature is raised to 50 C. A solution of chloropyrazine (50 g., 0.44 mole) in dimethylformamide (50 ml.) is added dropwise. The mixture is then heated for 3 hours. raising the temperature during this period to 120 C.

The reaction mixture is cooled to about 70 C. and water ml.) is added. The mixture is concentrated to a small volume and the residual liquid is diluted with icc-water (300 ml.) and extracted several times with ether. The combined ether extracts are washed with 5 percent hydrochloric acid. then with water. dried. and

1O evaporated. The resulting liquid is distilled. The product obtained is diethyl a-methylpyrazinylmalonate; b.p. l14-118 C. (0.5 mm.)

EXAMPLE V A sodium hydride-mineral oil suspension (54 /1; 3.1 g.. 0.069 mole) is stirred with three ml. portions of dry hexane. each portion being pipetted out to remove the mineral oil. Dimethylformamide (30 ml.. previously distilled and dried over a molecular sieve) is added through a pressure equalized addition funnel while a slow stream of nitrogen is passed through the mixture. The reaction vessel is cooled in an ice-bath while diethyl methylmalonate (12 g., 0.069 mole) is added dropwise to the stirred mixture. After the addition is complete. the ice-bath is replaced by an oil bath and the temperature is raised to 50 C. To the mixture is added dropwise 2-chloro-5-phenylpyrazine 10 g.. 0.053 mole) in warm dimethylformamide (55 ml.). After this addition is complete. the mixture is heated for 3 /2 hours during which time the temperature is raised to 120 C. The reaction mixture is cooled to about C. and water (4 ml.) is added. The mixture is concentrated to a small volume. and the residual liquid is diluted with 50 g. of ice and extracted with ether several times. The combined ether extracts are washed with 5 percent hydrochloric acid. then with water. and then dried and evaporated. The resulting oil is chromatographed on a column of 500 g. of Merck acidwashed alumina. Elution with benzene-hexane (4:1) through ethyl acetate-benzene (1:3) yielded diethyl a-methyl-S-phenylpyrazinylmalonate.

EXAMPLE VI A mixture of diethyl a-methyl-S-phenylpyrazinylmalonate (10.3 g.. 0.031 mole) and sodium cyanide (3.2 g., 0.065 mole) in dimethyl sulfoxide ml.) is stirred and heated at C. for hour. The reaction mixture is poured onto 300 g. of ice saturated with sodium chloride. and extracted several times with ether. The combined ether extracts are washed with water. dried. and evaporated. The resulting material is triturated with warm hexane and filtered. The hexane filtrate is evaporated and the resulting oil is distilled. The third fraction. which solidifies. is recrystallized from pentane and filtered at dry ice temperature. The product obtained is ethyl a-methyl-5phenylpyrazineacetate; m.p. 3840 C.

EXAMPLE VII EXAMPLE Vlll A mixture oldicthyl cx-methylpyrazinylmalonate (20 g, 0.08 mole). in 50% sodium hydroxide (40 ml.) is stirred and refluxed for 1% hours. The solution is cooled to room temperature. washed with ether. acidified. saturated with sodium chloride. and extracted sevcral times with ether. The combined ether extracts are dried and evaporated. The solid material is rccrystal lized by dissolving in warm benzene (with temperature below 50 C.) and then concentrating the solution under a stream of nitrogen with temperature below 50 C. The resulting mixture is filtered. The product obtained is a-methylpyrazineacetic acid; m.p. 9596 C. dec.

EXAMPLE lX A mixture of ethyl a-methyl-S-phenylpyrazineacetate (L g.. 0.0039 mole), water (8 ml.). and 50 percent aqueous sodium hydroxide (2 ml.) is refluxed for /4 hour. The reaction solution is cooled to room temperature and diluted with water. The solution is washed three times with ether, chilled in an ice-bath. rendered acidic with concentrated hydrochloric acid. and filtered. The solid material is recrystallized from benzene-hexane (temperature kept below 60 C.). The product obtained is oz-methyl-S-phenylpyrazineacetic acid; m.p. l05l07 C. dec.

EXAMPLE X Concentrated ammonium hydroxide (80 ml.) added to ethyl a-methylpyrazineacetate (8.0 g.. 0.044 mole) at ice-bath temperature. The mixture is stirred at room temperature for 2 hours. and then is saturated with sodium chloride and extracted with chloroform several times. The combined chloroform extracts are dried and evaporated. The solid material is recrystallized from ethyl acetate. The product obtained is a-methylpyrazineacetamide; m.p. 9698 C.

EXAMPLE XI A mixture of ethyl a-methyI-S-phenylpyrazineacetate (5.0 g., 0.02 mole) and concentrated ammonium hydroxide 100 ml.) is stirred at room temperature for 3 days in a stoppered flask. The reaction mixture is chilled and filtered. The solid material is recrystallized from benzene. The product obtained is a-methyl5- phenylpyrazineacetamideg m.p. l52-154.

EXAMPLE XI] A 12 g. (0.058 mole) sample of 5-(p-chlorophenyl)- pyrazinol is added to phosphorous oxychloride (40 ml.) containing sulfuric acid (3 drops) in a pressure bottle. The mixture is swirled briefly and heated in the open bottle at l C. for A hour to allow the evolution of hydrogen chloride. The bottle is closed and heated at about l C. for 4 hours. The bottle is cooled and the contents are poured onto a stirred mixture of 370 ml. of ice-water and 200 ml. of chloroform. The mixture is chilled and slowly neutralized with concentrated ammonium hydroxide; a sufficient quantity of 50 percent sodium hydroxide is added to render the mixture basic. The mixture is filtered through celite. the layers separated. and the aqueous layer is extracted twice more with chloroform. The combined chloroform extracts are dried and evaporated. The solid material is recrystallized from methanol. The product obtained is 2- chloro-5-(p-chlorophenyl)pyrazine; m.p. l45l4h C.

EXAMPLE Xlll A sodium hydridemiineral oil suspension (54 percent; 1.8 g. 0.04 mole) is stirred with three 25 ml. portionsdfdry hexane. each portion being pipettcd out to remove the mineral oil. Dimethylformamide (30 ml. previously distilled and dried over a molecular sieve) is added through a pressure equalized addition funnel while a slow stream of nitrogen is passed through the mixture. The reaction vessel is cooled in an ice-hath and diethyl methylmalonate (7 g.. 0.04 mole) is added dropwise to the stirred mixture. After the addition is complete. the ice-bath is replaced by an oil bath and the temperature is raised to 50 C. A solution of 2- chloro-5-(p-chloropheny] )pyrazine (8 g.. 0.0355 mole) in warm dimethylformamide ml.) is added dropwise. After this addition is complete. the mixture is heated for 3 hours during which time the temperature is raised to 120 C.

The reaction mixture is cooled to C. and water (3 ml.) is added. The mixture is concentrated to a small volume. The residual liquid is diluted with 40 ml. of icewater and extracted with ether several times. The combined ether extracts are washed with 5 percent hydrochloric acid, then with water. dried, and evaporated. The solid material is recrystallized from hexane. The product obtained is diethyl S-(p-chlorophenyU-amethylpyrazinylmalonate; m.p. 62-o4 C.

EXAMPLE XIV A mixture of diethyl S-(p-chlorophenyl)-a-methylpyrazinylmalonate (7.0 g. 0.019 mole) and sodium cyanide (2.0 g.. 0.04 mole) in dimethyl sulfoxide (60 ml.) is stirred and heated at l20 C. for 1 hour. The reaction mixture is poured into 200 ml. of ice-water saturated with sodium chloride. The material is extracted several times with ether. The combined ether extracts are washed with water. dried. and evaporated. The crude product is chromatographed on a column of acid washed alumina. Elution with benzene-hexane (1:4 through 4:] followed by benzene is undertaken. The solid material is recrystallized twice from pentane. The product obtained is ethyl S-(p-chlorophenyH-amethylpyrazineacetate; m.p. 4749 C.

EXAMPLE XV A mixture of ethyl 5 p-chlorophenyl l-a-methylpyrazineacetate (2.33 g.. 0.0080 mole). water (24 ml. and 50 percent aqueous sodium hydroxide (6 ml.) is refluxed for [V4 hours. The reaction mixture is diluted with about 30 ml. of water. washed three times with ether, chilled in an ice-bath, and then acidified with concentrated hydrochloric acid. The solid material is filtered and recrystallized from benzene-hexane (temperature kept below 50 C.). The product obtained is 5-(p-chlorophenyl J-a-methylpyrazineacetic acid; m.p. ll ll 12 C. dec.

EXAMPLE XVI A mixture of ethyl 5(pchlorophenyl)-a-methylpyrazineacetate (0.90 g.. 0.003l mole) and concentrated ammonium hydroxide (50 ml.) is stirred in a stoppered flask for 3 days at room temperature. The reaction mixture is chilled and filtered. The solid material is recrystallized from benzene. The product obtained is 5-( p-chlorophenyl )-0z mcthylpyrazineacetamide; m.p. l )2l93 C.

EXAMPLE XVll A solution olethyl cemethyl-S-phcnylpyrazincacctate. (3.0 g. 0.012 mole) in ether (30 ml.) is added to a stirred solution of sodium amide (0.5. ().0l 3 mole) in liquid ammonia (50 ml.) at dry ice-acetone tempera ture. The mixture is allowed to reflux for A. hour. Methyl iodide (1.7 g.. 0.012 mole) is added. The mixture is stirred for l hour. The ammonia is allowed to evaporate. The residue is diluted with ether. Ammonium chloride is added until the mixture is neutral. The mixture is poured into dilute hydrochloric acid. The ether layer is separated and washed successively with sodium bisultite solution. sodium bicarbonate solution. and water. The ether solution is dried and evaporated. The solid material is recrystallized from pentane. The product obtained is ethyl a.a-dimethyI-S-phenylpyrazineacetate.

EXAMPLE XVIII Using the procedure of Example XI and replacing ethyl oz-methyl--phenylpyrazineacetate with an equivalent amount of ethyl a.a-dimethyI-S-phenylpyrazineacetate. the product obtained is ma-dimethyl-S- phenylpyrazineacetamide.

EXAMPLE XIX Using the procedure of Example IX and replacing ethyl a-methyl-S-phenylpyrazineacetate with an equivalent amount of ethyl a.a-dimethyl-5-phenylpyrazineacetate. the product obtained is a.a-dimethyl-5-phenyl-pyrazineacetic acid.

EXAMPLE XX EXAMPLE XXI A mixture of a-methyl-S-phenylpyrazineacetic acid (3.0 g.. 0.013 mole) and thionyl chloride ml.) is stirred and warmed at about 60 for V2 hour. The reaction solution is cooled in an ice-bath. A solution of morpholine l.2 g., 0.0l4 mole) in benzene (75 ml.) is added. The mixture is warmed on the steam bath for A hour. cooled. and diluted with water. The aqueous mixture is extracted several times with ether. The combined ether extracts are washed with dilute hydrochloric acid. dilute sodium bicarbonate. and water. and then dried and evaporated. The solid residue is recrystallized from benzene. The product obtained is 4-(amethyl-S-phenylpyra2ineacetyl )morpholine.

EXAMPLE XXII 3-Hydroxy-5-phenylpyrazine-2-carboxamide is prepared by the method of Dick. Wood and Logan. 1. Chem. Soc.. 2l3l (I956). The carboxamide is converted to fi-phenylpyrazinol by the method ofJezo and Luzak. Chem. Zvest.. 22. I90 l968) using 80 percent sulfuric acid at I80 C. Using the procedure of Example III and replacing 5-phenylpyra7inol with an cquivalent amount of o-phenylpyravinol. the product obtained is Z-chloro-fi-phenylpyrazine. Using the procedure of Example V and replacing Z-chloro-S- phenylpyrarine with an equivalent amount of Z-chloroo-phenylpyrayine. the product obtained is diethyl a-methyl-o-phenylpyrazinylmalonate. Using the procedure of Example VI and replacing diethyl a-methyl-S- phenylpyrazinylmalonate with an equivalent amount of diethyl a-methyl-o-phenylpyrazinylmalonate. the product obtained is ethyl a-methyl o-phenylpyrazineacetate. Using the procedure of Example IX and replacing ethyl oz-methyl-5-phenylpyrazineacetate with an equivalent amount of ethyl a-methyl-o-phenylpyrazineacetate. the product obtained is a-methyl-ophenylpyrazineacetic acid. Using the procedure of Example XI and replacing ethyl oz-mcthyLS -phenylpyrazineacetate with an equivalent amount of ethyl a-mcthyl-o-phenylpyrazineacetate. the product obtained is a-methyl-o-phenylpyrazineacetamide.

EXAMPLE XXIII p-Chlorophenylglyoxal hydrate is treated with an aqueous sodium bisulfite solution. The mixture is then heated with an equimolar portion of aminomalonamide dissolved in water. The product obtained is 3-hydroxy- 5-(p-ehlorophenyl)pyrazine-Z-carboxamide. The carboxamide is heated at l C. in 80 percent sulfuric acid. The product obtained is 6-( p chlorophenyhpyrazinol. Using the procedure of Example III and replacing S-phenylpyrazinol with an equiva lent amount of o-(p-chlorophenyl )-pyrazinol the product obtained is 2-chloro-6-(p-chlorophenyl)pyrazine. Using the procedure of Example V and replacing 2-chloro-S-phenylpyrazine with an equivalent amount of 2-chloro-6(pchlorophenyl)pyrazine. the product obtained is diethyl amethyl-6-(p-chlorophenyl)- pyrazinylmalonate. Using the procedure of Example VI and replacing diethyl cr-methyl-S-phenylpyrazinylmalonate with an equivalent amount of diethyl a-methylfi-(p-chlorophenyl)pyrazinylmalonate. the product obtained is ethyl a'methyl-6-(p-chlorophenyl)pyrazineacetate. Using the procedure of Example IX and re placing ethyl a-mcthyl-S-phenylpyrazineacetate with an equivalent amount of ethyl oz-methyl-b-(pchlorophenyl )-pyrazineacetate. the product obtained is a-methyI-6( p-chlorophenyl )pyrazineacetic acid. Using the procedure of Example XI and replacing ethyl a-methyl-S-phenylpyrazineacetate with an equivalent amount of ethyl a-methyl-6-(p chlorophenyl)pyrazineacetate. the product obtained is a-methyl-6-( pchlorophenyl)pyrazineacetamide.

EXAMPLE XXIV Using the procedure of Example V and replacing 2-chloro-S-phenylpyrazine with an equivalent amount of Z-chloro-3-phenylpyrazine (prepared by the method of Karmas and Spoerri. .I. Am. Chem. Soc.. 78. 4071, 1956). the product obtained is diethyl a-methyLS- phenylpyrazinylmalonate. Using the procedure of Ex ample VI and replacing diethyl a-methyl-S-phenylpyrazinylmalonate with an equivalent amount of diethyl a-methyl-3-phenylpyrazinylmalonate. the product obtained is ethyl a-methyl-3-phenylpyrazincacetate. Using the procedure of Example IX and replacing ethyl a-methyl-5-phenylpyrazineacetate with an equivalent amount of ethyl a-methyl-3-phenylpyrazineacetate. the product obtained is a-methyl3- phenylpyra7ineacctic acid. Using the procedure of Example XI and replacing ethyl a-methyl-S-phenylpyrazineaectate with an equivalent amount ofethyl cx-methyl-3-phenylpyrazineacetatc. the product obtained is d-methyl-3-phenylpyrazineacetamide.

EXAMPLE xxv 2-Chloro-3-(p-chlorophenyl)pyrazine is prepared by the method of Karmas and Spoerri (loc. cit. I. using 3- (p-chlorophenyl)pyrazinol as the starting material. Starting with this material and using the procedures of Examples V. VI. IX. and XI. the products obtained are diethyl amethyl-3-(p-chlorophenyl)pyrazinylmalonate. ethyl a-methyl3-(p-chlorophenyl)pyrazineacetate. cr-methyl-3-(p-chlorophenyl)pyrazineacetic acid. and a-methyl-fi-l p-chlorophenyl )pyrazineacetamide.

EXAMPLE XXVI a-Bromocyclohexane acetyl bromide is prepared by the Hell-Volhard-Zelinsky reaction (Hell. Ber.. 14. 89I, I88]; Zelinsky. Ber.. 20. 2026. I887; Volhard. Ann.. 242. 14]. 1887) starting with cyclohexylacetic acid. The a-bromocyclohexane acetyl bromide is reacted with ammonia to produce a-aminocyclohexylacetamide. Equimolecular portions of percent aqueous glyoxal and a-aminocyclohexylacetamide are dissolved in aqueous methanol. and the mixture is treated with sodium hydroxide in the cold. The product obtained is 3-cyclohexylpyrazinol. Starting with this product and using the procedures of Examples III. V. VI, IX. and XI. the products obtained are 2-chl0ro-3- cyclohexylpyrazine. diethyl oz-methyl-3-cyclohexylpyrazinylmalonate. ethyl a-methyl-3-cyclohexylpyrazineacetate. u-methyl-3-cyclohexylpyrazineacetic acid. and a-methyl-3-cyclohexylpyrazineacetamide.

EXAMPLE XXVII EXAMPLE XXVIII Using the procedure of Example I and replacing phenylglyoxal hydrate with an equivalent amount of cyclohexylglyoxal hemihydrate, the product obtained is S-cyclohexylpyrazinol. Starting with this material and using the procedures of Examples III. V. VI. IX, and XI. the products obtained are 2-chloro 5- cyclohexylpyrazine, diethyl a-methyl-S-cyclohexylpyrazinylmalonate. ethyl a-methyl-5 cyclohexylpyrazineacetate. a-methyl fi-cyclohexylpyrazineacetic acid. and amethyl-5-cyclohexylpyrazineacetamide.

EXAMPLE XXIX Using the procedure of Kornblum and Frazier, 1. Am. Chem. Soc. 88. 865 I966). substituted phenylglyox als, such as p-methylphenylglyoxal, p-methoxyphenylglyoxal, m-chlorophenylglyoxal. ochlorophenylglyoxal. p-fluorophenylglyoxal. 2.5- dichlorophenylglyoxal. p-trii'luoromethylphenylglyoxal. 2.3dimethylphenylglyoxal. and 2.3-dimethoxyphenylglyoxal. are prepared from the corresponding substituted acetophenones. The substituted phenyl- EXAMPLE XXX Using the procedure of Example XXIII and replacing p-chlorophenylglyoxal with substituted phenylglyoxals such as those identified in Example XXIX. the corresponding 6-(substituted-phenyl)pyrazinols are obtained. Correspondingly by the procedures of Examples XII. XIII. XIV. XV. and XVI. the corresponding 2-chloro-6-(suhstituted-phenyl)pyrazines. diethyl 01-methyl-6-(substituted-phenyl )-pyrazinylmalonates. ethyl-a-methyl-6-( substituted-phenyl )-pyra7.ineacetates, a-methyl-6-( substituted-phenyl )pyrazineacetic acids. and a-methyl-6-(substitutedphenyl)pyrazineacetamides are obtained.

EXAMPLE XXXI Using the procedure of Karmas and Spoerri (J. Am. Chem. Soc. 78. 4(l7l, I956). and starting with pyrazi no] and substituted phenyldiazonium chlorides. such as p-methylphenyldiazonium chloride, p-methoxyphenyldiazonium chloride. m-chlorophenyldiazonium chlo ride. o-chlorophenyldiazonium chloride, pfluorophenyldiazonium chloride. 2.5- dichlorophenyldiazonium chloride. p-trifluoromethylphenyldiazonium chloride. 2.3-dimetbylphenyldiazonium chloride. and 2.3-dimethoxyphenyldiazonium chloride. the corresponding 3-(substituted phenyl)pyra2inols are prepared. Starting with these materials and using the procedures of Examples XII. XIII. XIV. XV. and XVI. the products obtained are the corresponding 2-chloro-3-( substitutedphenyl )pyrazines. diethyl a-methyl- 3 substituted phenyl )pyrazinylmalonates. ethyl oz-methyl-B- (su bstitutedphenyl )pyrazineacetates. amethyl-3- (substituted-phenyl)pyrazineacetate acids. and oz-methyl-3-(substituted-phenyl )pyrazineacetamides.

EXAMPLE XXXII Using the procedure of Example XXI and replacing morpholine with an equivalent amount respectively of methylamine. dimethylamine. ethylamine. diethylamine. isopropylamine. and n-butylamine. the corresponding N-methyL, N,Ndimethyl-. N-ethyl-. N.N- diethyl-Q N-isopropyL and N-n-butyl-acetamides are obtained. Repeating this procedure and replacing a-methyl-5-phenylpyrazineacetic acid with equivalent amounts of a-methyl-b-phenylpyrazineaeetic acid and amethyl-3-phenylpyrazineacetic acid. the correspond ing N-substituted amides ol these compounds are obtained.

EXAMPLE XXXIII Using the procedure of Example IV. replacing diethyl methylmalonate with an equivalent amount of diethyl l7 nialonatc and replacing chloropyrazine with equivalent amounts of Z-chloro-S-phenylpyra7ine. l-chloro-ophenylpyrazine. Z-chloro-3-phenylpyrazine. Z-chloro- 5-cyclohexylpyrazine. 2-chloro-6-cyclohexylpyrazine. 2-ehloro-3-cyclohexylpyrazine. Z-chlorofi-(pchlorophenyl )pyrazine. 2-chloro-h-( pchlorophenyl)pyrazine. Z-chloroJ-(pchlorophenyl)pyrazine. Z-chloro-S-(w chlorophenyl )pyrazine. 2-chloro-5-( pfluorophenyl )pyrazine. 2-chloro-5-( p-methoxyphenyl )pyrazine. 2-chloro-5-( 2.5- dichlorophenyl)pyrazine. 2-chloro-5-(p-trifluorome thylphenyl)pyrazine, Z-chloro-S-(pmethylphenyl )pyrazine. 2-chloro-5-( m chlorophenyl)pyrazine. and 2-chloro-5-(2.3-dimethoxl yphenyl )pyrazine. the corresponding diethyl pyra2inylmalonates are produced. Starting with these compounds and using the procedures of Examples Vl, IX and XI. the products obtained are the corresponding ethyl pyrazine-acetates. pyrazineacetic acids. and pyrazineacetamides.

EXAMPLE XXXIV Using the procedure of Example IV. replacing diethyl methylmalonate with an equivalent amount of diethyl malonate. the product obtained is diethyl pyrazinylmalonate. Starting with this material and using the procedures of Examples VI and IX the products obtained are ethyl pyrazineacetate and pyrazineacetic acid.

EXAMPLE XXXV Using the procedure of Example XVI] and replacing methyl iodide with equivalent amounts of ethyl iodide. isopropyl. iodide. and n-hutyl iodide. the products obtained are ethyl eacetate. ethyl a-methyl-a-isopropyl-S-phenylpyrazineacctate. and ethyl a-methyl-a-(n-butyl)-5-phenylpyrazineacetate.

EXAMPLE XXXVI Using the procedure of Example IX and replacing ethyl a-methyl-5-phenylpyrazineacetate with equiva lent amounts of the products of Example XXXV. the

products obtained are a-methyl-a-ethyl-S- phenylpyrazineacetic acid. a-methyl-a-isopropyl-S- phenylpyrazineacetic acid and a-methyl-a-(n-hutyl )-5- phenylpyrazineacetic acid.

EXAMPLE XXXVll Using the procedure of Example XI and replacing ethyl a-methyl-5-phenylpyrazineacetate with equivalent amounts of the products of Example XXXV. the products obtained are a-methyl-a-ethyl-5- phenylpyrazineacetamide. phenylpyrazineacetamide. and a-methyl-a-( n-butyl )-5- phenylpyrazineacetamide.

EXAMPLE XXXVI" Using the procedure of Example V. employing 2- chloro-R-pyrazines having the formula a-methyl-a-ethylS-phenylpyrazina-methyl-a-isopropyl-S- wherein R has the same value as in Formula hereinabove. and replacing diethyl methylmalonate with equivalent amounts of diethyl ethylmalonate. diethyl isopropylmalonate. and diethyl n-butylmalonate. the products obtained are diethyl wsuhstituted-R- pyrazinylmalonates having the formula wherein R has the same value as above and or is respectively ethyl. isopropyl. and n-butyl. Starting with these products and using the procedure of Example Vl. the products obtained are the corresponding ethyl a-substituted-R-pyrazineacetates. Starting with these products and using the procedures of Examples IX and XI. the corresponding acetic acids and acetamides are obtained.

EXAMPLE XXXIX Using the procedure of Example XVI]. employing the ethyl a-substituted-R-pyrazineacetates of Example XXXVI". and replacing methyl iodide with equivalent amounts of ethyl iodide. isopropyl iodide. and n-hutyl iodide. the products obtained are the ethyl or. oF-diwherein R has the same value as in Formula I hereinabove and wherein a and a are the following:

ethyl ethyl isopropyl ethyl n-hutyl ethyl isopropyl isopropyl isopropyl n-butyl n-butyl n-hutyl The corresponding 0:. a -disubstituted-R- pyrazineacetic acids are prepared by the method of Example lX. The corresponding a.a'--disubstituted'R- pyrazineacetamides are prepared by the method of Example XI.

EXAMPLE XL Sodium hydride [54 percent in mineral oil; 6.1 g.. 0.14 mole) is stirred with three portions (60 ml.) of dry hexane. each portion being pipetted out to remove the mineral oil. Dimethylformamide (previously distilled and dried over a molecular sieve; 55 ml.) is added through a pressureequalized addition funnel while a slow stream of nitrogen is passed through the mixture. The reaction vessel is placed in an ice-bath and diethyl methylmalonate (24 g.. 0.14 mole) is added dropwise to the stirred mixture. After the addition is complete. the ice-hath is replaced by an oil bath and the temperature is raised to 50 C. A solution of 5 chloro-2.3-

l9 diphenylpyrazine (28 g.. 0.l 1 mole) in warm dimcthylformamide (I I ml.) is added dropwise. The mixture is heated for 3% hours while the temperature is raised to l20 C.

The reaction mixture is cooled to about 80 C. and water (8 ml.) is added. The mixture is concentrated to a small volume. and the residual liquid is mixed with 800 g. of ice and extracted several times with ether. The combined ether extracts are washed with percent hydrochloric acid. then with water. dried. and evapo rated. The resulting oil is chromatographed on a column of acid-washed alumina. Elution with benzenehexane (3:2 thru I00 percent benzene) is undertaken. The product obtained is diethyl a-methyl-S.b-diphenylpyrazinylmalonate.

EXAMPLE XLl A mixture of diethyl a-methyl-Sb-diphenylpyrazinylmalonate. (4.5 g.. 0.01 I mole) and sodium cyanide (l.l g. 0.023 mole) in dimethyl sulfoxide (40 ml.) is stirred and heated between l40l65 C. for 1 hour. The reaction mixture is poured onto I00 g. of ice. saturated with sodium chloride. and extracted several times with ether. The combined ether extracts are washed with water. dried. and evaporated. The resulting oil is purified by elution on a column of acid washed alumina with benzene-hexane (4:1 thru I00 percent benzene). The product obtained is ethyl a-methyl-Sf diphenylpyrazineacetate.

EXAMPLE XLll Concentrated ammonium hydroxide (250 ml.) is added to a solution of ethyl a-methyl-S.6-diphenylpyra zineacetate (9.0 g.. 0.027 mole) in absolute ethanol (250 ml.). and the mixture is stirred in a stoppered flask for 5 days. The mixture is kept at room temperature with occasional warming to 50 C. Additional concentrated ammonium hydroxide I00 ml.) is added to the stirring mixture on the fourth day. The stopper is removed. the mixture is diluted with another 100 ml. of concentrated ammonium hydroxide. and then warmed at 50 C. for IS minutes. The mixture is chilled and filtered. The ammoniacal ethanol filtrate is diluted with a large volume of water. Sodium chloride is added. and the mixture is extracted several times with chloroform. The chloroform solution is dried and evaporated. The solid material is chromatographed on a column of 225 g. of acid washed alumina. Subsequent fractions are eluted with ethyl acetate and with ethyl acetate methanol (9/1). The purest fraction is recrystallized from ethanol-water. The product obtained is a-methyl- 5.6-diphenylpyrazineacetamide; mp. l23125 C.

EXAMPLE XLlll A mixture of ethyl wmethyl-S,o-diphenylpyrazincacetate (1.4 g.. 0.004 mole). 95% ethanol ml). water (3 ml. and 50% sodium hydroxide (3 ml.) is refluxed for 4 hours. The ethanol is evaporated and the aqueous residue is diluted with water and washed sev eral times with ether. The aqueous layer is acidified in the cold with concentrated hydrochloric acid. The product is filtered and purified by careful recrystalli ration from cther-hexane or by dissolving in aqueous base and reforming with concentrated acid. The product obtained is mmethyl-S.(Hliphenylpyrarincacctic acid; m.p. l27l2t C. dec.

bl J

20 IIXAMPII: xi iv A mi\lurc ofdiethyl d-methyl-S-phenylpyrazinylmalonatc a. 0.012 mole) in water (32 ml.) containing sodum hydroxide (8 ml.) is stirred and refluxed for l /e hours. The solution is evaporated to about half the original volume and chilled. The crystals formed are the disodium salt of a-methyl-S-phenylpyrazinylmalonic acid. Repeating the process but acidifying the solution after refluxing. and then adding sodium hydroxide, evaporating to half the original volume and chilling. the sodium salt of a-methyl-S- phenylpyrazineacetic acid is recovered. These procedures are repeated using ammonium hydroxide and calcium hydroxide respectively and adjusting the reflux time to obtain the corresponding ammonium and cal cium salts of a-mcthyl5-phenylpyrazinylmalonic acid and u-methyl-S-phenylpyrazineacetic acid. In a similar manner. the salts of the other malonic acids and acetic acids of this invention are prepared.

EXAMPLE XLV A quantity of cit-methyl-5.b-diphenylpyrazineacetic acid is heated at about 130 C. for [5 minutes. The resulting melt is diluted with water and extracted several times with ether. The ether solution is dried and evaporated. The solid material is recrystallized from per cent ethanol. The product obtained is 2.3-diphenyl-5- ethylpyrazine; m.p. l02-l04 C.

EXAMPLE XLVl Using the procedures of Example XXVI and thereafter Examples lll. V. VI, IX. and XI as shown in Exam ple XXVI. and replacing cyclohexylacetic acid with an equivalent amount of cyclopcntylacetic acid. the products obtained are 3-cyclopentylpyrazinol, 2-chloro-3- cyclopentylpyrazine. diethyl a-methyl-3-cyclopentylpyrazinylmalonate. ethyl a-methyl-3-cyclopentylpyrazineacetate. a-methyl-3-cyclopentylpyrazineacetic acid. and a-methyl-3-cyclopentylpyrazineacetamide.

EXAMPLE XLVll Using the procedure of Example XXVll and thereafter Examples "I, V. V]. IX, and XI as shown in Exam ple XXVll. and replacing cyclohexylglyoxal with an equivalent amount of cyclopentylglyoxal. the products obtained are b-cyclopentylpyrazinol. 2-chloro-6- cyclopentylpyrazine. diethyl a-methyl-o-cyclopentylpyrazinylmalonate. ethyl a-methyLh-cyclopentylpyrazineacetate. a-methyl-fi-cyclopcntylpyrazineacctic acid. and (x-methyl-(w-cyclopentylpyrazineacetamide.

EXAMPLE XLVlll Using the procedure of Example XXVlll and thereafter Examples "I. V. VI. IX. and X] as shown in Example XXVlIl. and replacing cyclohcxylglyoxal with an equivalent amount of cyclopentylglyoxal. the products obtained are 5-eyclopentylpyrazinol. Z-chIoro-S- cyclopentylpyrayinc. dicthyl amethyl-5-cyclopentylpyrayinylmalonatc. ethyl wmethyl-5cyclopentylpyralineacctate. u-mcthylfi-cyclopentylpyrazineacetic acid. and wmethyl-i-cy.clopentylyprazineacctamidc.

EXAMPLE XLIX A mixture of dicthyl u-ethyl-S-phenylpyrazinylmalonate( l8 g. 0.053 mole). 40 ml. ol'50 percent sodium hydroxide. and lo ml. of water is refluxed for 2 hours.

The mixture is then diluted with water. washed several times with ether. and acidified with cold concentrated hydrochloric acid. The solid material is recovered by shoulder Certain of the novel compounds of this invention have been found to possess pharmacological activity as anti-inflammatory agents. These are identified by Example number in Table llv The test used is known as the kaolin-induced paw edema test. This test measures the ability of a compound. when administered in a single oral dose. to inhibit the swelling of the rat paw injected with a standard amount (0.1 ml.) of IO percent kaolin suspension in saline. For comparative purposes. the activity of the compound to be tested is measured against that produced by the known anti-inflammatory agent. phenylbutazone. In this assay. the test compound (04 percent suspension or 0.4 percent solution. depending on the compound) and phenylbutazone (0.4 percent solution) are administered in saline. Male Holtzman rats are used in the assay. The results are recorded in terms of percent inhibition produced by the compound and by phenylbutazone. The percent inhibition is calculated from the milliliters of mercury displaced as the edema develops in the paw. The paw is placed in a pool of mercury immediately after injection with the kaolin suspension, and a reading is taken on the quantity of mercury displaced. The animal is then returned to the cage. allowing the edema to develop. After 6 hours. the paw is again immersed in mercury and the quantity of mercury displaced is again measured. The method is described in J. Pharm. and Experimental Therapeutics.

l6]. l9fi20l (196R).

filtration and crystallized from benzenehexane below 50 Cv The product is wethyl-fi-phenylpyrazineacetic acid; m.p. 909l C. dec.

EXAMPLE I.

. l5 UsIng the procedure of Example XL. replacing dI- ctbyl mcthylmalonatc with an equivalent amount of diethyl ethylmalonate. the product obtained is diethyl a-ethyl-S.b-diphenylpyrazinylmalonate. Starting with this product and using the procedures of Examples XLl. XLlll. and XLII. the corresponding acetate. acetic acid. and acetamide are obtained.

TABLE I )\rna\v E\i\l1l||lt. No tMu) e l\ 2m 7.700 26% (1.500 300 l.l(|lI :SI 5.41m :xs H.500 \l :4 14,400

2% I Lnnt) \ll 2m 7.0m)

37a- 5 sun 30X 790 \'III 267 6.700 272* (glint) in? am I\ 2-1) I 5mm 40 2s I2.2uo :hh 71K) :71 (Jun sou um (I :4 15.400 29o 12.31) XIII 255 Issue 2s? menu 305* Ill-Jon Xl\ 254 lrwoo :ss lihllu 305* H.800 xv 254 18.000

lss mum 5Q 3110* mono XV] 254 17.000 Zsx W300 mm 13.2no

Example v IM Xi XIII xn TABLE II No. Dose (oral) Mg/Kg Inhibition .4 of Rats laumiplc Phcnylhutahmc livamplc Phenylbulavonc In I00 In 43 HI lllU IUU 5U 47 HI lllll lllU 4U 53 I0 I00 Inn St) 34 It) llio Hi0 3s 3-1 HI lllU Hit) 4i 5!) 10 I00 100 27 4-4 In In() I00 41 (1| HI illil UK] 56 4% In Int) lll() ZI 4| 23 We claim: I. A member selected from the group consisting of a compound of the formula c a N wherein R is a member selected from the group consisting of hydrogen and loweralkyl; R is a member se- UNITED STATES PATENT AND TRADEMARK OFFICE PATENT NO.

DATED INVENTOR(S) CERTIFICATE OF CORRECTION 3,9 1, 5 August 26, 1975 Schwartz, Norman, et al.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

[SEAL] In Column 2, line 57, "and" should read In Column 3, in diagram, delete the letter "A" from lower lefthand formula In Column 5, line 19, "illustrating" should read illustrates In Column 9, line 24, "To a phosphorous" should read To phosphorous In Column 16, line &9, "pyrazineacetate acids" should read pyrazineacetic acids In Column 21, omitted entire paragraph preceding Table I Table I shows the ultraviolet light absorption characteristics of the compounds identified in the Examples. The solvent employed is methanol.

Signed and Sealed this Twenty-fifth Day Of October 1977 A nest:

RUTH C. MASON Arresting Officer 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA
 2. Diethyl Alpha -methyl-5,6-diphenylpyrazinylmalonate.
 3. Ethyl Alpha -methyl-5,6-diphenylpyrazineacetate.
 4. Alpha -Methyl-5,6-diphenylpyrazineacetamide.
 5. Alpha -Methyl-5,6-diphenylpyrazineacetic acid. 